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,
,
* Inflammation Program, and
Department of Internal Medicine, University of Iowa and Iowa City Veterans Affairs Medical Center, and
Department of Microbiology, University of Iowa, Iowa City, IA 52242; and
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202-3591
The bactericidal/permeability-increasing protein (BPI) is thought to play an important role in killing and clearance of Gram-negative bacteria and the neutralization of endotoxin. A possible role for BPI in clearance of cell-free endotoxin has also been suggested based on studies with purified endotoxin aggregates and blood monocytes. Because the interaction of BPI with cell-free endotoxin, during infection, occurs mainly in tissue and most likely in the form of shed bacterial outer membrane vesicles ("blebs"), we examined the effect of BPI on interactions of metabolically labeled ([14C]-acetate) blebs purified from Neisseria meningitidis serogroup B with either human monocyte-derived macrophages or monocyte-derived dendritic cells (MDDC). BPI produced a dose-dependent increase (up to 3-fold) in delivery of 14C-labeled blebs to MDDC, but not to monocyte-derived macrophages in the presence or absence of serum. Both, fluorescently labeled blebs and BPI were internalized by MDDC under these conditions. The closely related LPS-binding protein, in contrast to BPI, did not increase association of the blebs with MDDC. BPI-enhanced delivery of the blebs to MDDC did not increase cell activation but permitted CD14-dependent signaling by the blebs as measured by changes in MDDC morphology, surface expression of CD80, CD83, CD86, and MHC class II and secretion of IL-8, RANTES, and IP-10. These findings suggest a novel role of BPI in the interaction of bacterial outer membrane vesicles with dendritic cells that may help link innate immune recognition of endotoxin to Ag delivery and presentation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants PO144642 and AI59372 from the U.S. Public Health Service (to J.P.W.).
2 Address correspondence and reprint requests to Dr. Jerrold P. Weiss, Roy J. and Lucille A. Carver College of Medicine, University of Iowa and the Veterans Affairs Medical Center, Inflammation Program, Oakdale Research Campus, 2501 Crosspark Road, Coralville, IA 52241. E-mail address: Jerrold-Weiss{at}uiowa.edu
3 Abbreviations used in this paper: BPI, bactericidal/permeability-increasing protein; LBP, LPS-binding protein; HSA, human serum albumin; LOS, lipo-oligosaccharide; MDM, monocyte-derived macrophage; DC, dendritic cell; MDDC, monocyte-derived DC; OM, outer membrane; LAMP-1, lysosome-associated membrane protein-1; TRITC, tetramethylrhodamine isothiocyanate.
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